During systemic autoimmune diseases, only certain autoantibodies are produced; for example anti-DNA occurs in lupus but not Rheumatoid Arthritis. Although recent and classic work has shown that certain self- reactive B cells can be anergized or eliminated; a breakdown of these tolerance mechanisms is unlikely to explain why the autoantibody response focuses on certain autoantigens while tolerance is apparently maintained towards other autoantigens. Indeed, we have little insight into why systemic autoimmunity displays target specificity, even though an understanding of this point should be central to any models of autoimmune pathogenesis. Furthermore, while transient benign autoimmunity occurs in normal individuals, pathogenic autoimmunity is usually a chronic process. Presumably there are mechanisms to downregulate existing autoimmune responses, but these have yet to be elucidated. To address these issues, we have developed a transgenic mouse model in which nearly all of the B cells express, as surface IGM, the RF specificity of AM14, an autoantibody derived from an autoimmune MRL/lpr mouse. A key feature of the RF system, in contrast to other disease-related autoantibodies, is the ability to manipulate both the antigen and antibody. This can be done because anti-IgG2a RFs from autoimmune mice--such as AM14-- display allotype specificity. Thus, unlike other disease-related autoantibodies, RR B cells can be studied in the presence and absence of the autoantigen by crossing the transgenes onto IgH allotype congenic strains. Using this model we have recently demonstrated that autoreactive RF B cells are not deleted in normal (non-autoimmune) transgenic mice. New preliminary data has also shown that autoreactive RF B cells can participate in a primary in vivo immune response, suggesting that autoreactive RF B cells are not anergized. This represents a new phenotype for an autoreactive B cell and suggests that systemic autoimmunity could focus on certain targets if B cells specific for these are not ordinarily tolerized. Since autoreactive RF B cells can make primary responses, this model provides the opportunity to explore potential mechanisms that prevent an initial autoimmune response from escalating into a chronic, memory-type response. I propose to use this model and to develop analogous models to: 1) Determine whether autoreactive RF B cells can participate in primary immune responses and develop into memory cells with accompanying isotype switch, mutation and affinity maturation. 2) Determine whether B cells expressing an RF of very high affinity (isolated from an alloimmunized mouse) are deleted or anergized or whether, alternatively, the RF specificity is inherently less prone to B cell tolerance regulation. 3) Determine the effects of an autoimmune genetic background, as represented in this case by the single gene model lpr, on the regulation of an autoreactive B cell. In particular, in this Aim we can determine the role of self-antigen (via IgH congenic strains which either have or lack the autoantigen) in driving potential autoreactive B cell activation. The prime significance of this work is that understanding the basis for selective breakdown of tolerance in autoimmunity would provide insight into basic mechanisms of B cell tolerance and how these fail in autoimmune disease.